Project Summary Broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) show great promise in HIV prevention and therapy as they potently neutralize a significant breadth of globally circulating HIV strains. A number of animal experiments and clinical trials have demonstrated the ability of bNAbs to confer protection from viral challenge and reduce viremia of established infections. BNAbs can inhibit HIV infection by blocking viral attachment or membrane fusion; however, recent work suggests that the fragment crystallizable (Fc) region of antibodies may also contribute significantly to bNAb-mediated HIV inhibition through interactions with innate immunity. Here I propose to use in vitro cell-based assays to determine the extent to which different HIV bNAbs engage effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), complement- dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP). Using humanized mouse models, I will study the impact of altered effector function activity on bNAb-mediated protection against both intravenous and mucosal HIV transmission as well as viral suppression and reservoir clearance. This work will elucidate the contribution of Fc functions to effective HIV inhibition and will explore the potential of bNAbs with enhanced effector functions to yield greater efficacy in vivo. Together these studies will contribute to our understanding of the role of innate immunity during HIV neutralization and may contribute towards improving bNAbs for treatment and prevention in patients.